Upon retirement of the Section Chief David Ted George, MD, the CATE Section has been led by Lorenzo Leggio, MD, PhD, MSc, in Acting Chief capacity. 1) Corticotropin-releasing hormone receptor 1 (CRH1) antagonism and stress-induced craving in alcohol dependent women with high anxiety. As alcoholism evolves, a shift occurs from positively to negatively reinforced alcohol use. Along the way, stress becomes a major trigger of relapse and excessive alcohol intake. Corticotrophin-releasing hormone (CRH) plays a major role in this state. The team negotiated a CRADA with GlaxoSmithKline, obtained an IND, and initiated a protocol that uses GSK561679 (CRH antagonist) as a translational tool in anxious female alcoholics (preclinical toxicology studies show that its use leads to a suppression of spermatogenesis, thus precluding its use in males). The hypothesis is that GSK561679 will reduce alcohol craving in response to the combined challenges of the Trier Social Stress Task, alcohol-cue exposure, and guided imagery scripts. We will also examine whether GSK561679 will reduce spontaneous craving, reduce fMRI BOLD responses to negative affective stimuli within the ventral visual stream, medial temporal lobe and/or the anterior insula, and modulate blood markers of endocrine function in a manner indicative of anti-stress effects. 2) Role of proinflammatory signaling in alcohol craving. Ethanol-induced activation of innate immunity has emerged as a potential mechanism for understanding the pathophysiology of alcoholism. The objective of the present study is to evaluate the role of proinflammatory signaling in alcohol craving. The peroxisome proliferator-activator receptor gamma agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration, which activates proinflammatory signaling, will be used as a novel challenge and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response. In addition to the ongoing research, Dr. Leggio and his CPN group, and in collaboration with the CATE group, as well as with all other clinical LCTS sections (HP and BEI), have developed a new screening protocol, 14-AA-0181, Unit and Clinic Evaluation, Screening, Assessment, and Management Un.Cl.E. S.A.M.. Under Dr. Leggio's leadership, this study represents the new natural history protocol for NIAAA with the main objectives of providing assessment, clinical care, evaluation, characterization and screening. The specific goals of this protocol are the following: 1) to provide clinical care, including but not limited to medically assisted withdrawal from alcohol (detoxification), as well as standard behavioral and/or pharmacological therapies where indicated to those who wish to receive treatment for alcohol use disorders (AUD) and related clinical conditions; 2) to gather characterization measures for individuals wishing to participate in this protocol and in future NIH protocols (for which this protocol serves as the screening protocol), including a standardized set of clinical, behavioral, biochemical and structural MRI-based phenotypic assessments, as well as whole genome genotypes; 3) to screen and evaluate individuals wishing to participate in NIH clinical protocols (both those providing treatment and those that do not provide treatment for AUD) for which the present protocol serves as the screening platform. Participants may be individuals with no current or past AUD, as well as individuals who meet current or past DSM criteria for AUD. Healthy volunteers and other volunteers will also be enrolled in this protocol; and 4) finally, this protocol may also serve for training purposes, as it may provide opportunities for training of fellows and other staff members of the NIAAA Clinical Programs.